Arthrofactin for the treatment of acne

ABSTRACT

The present invention relates to a mixture of arthrofactin or of a composition containing it and to the use thereof for the treatment of acneic skin.

The present invention relates to the use of a mixture of arthrofactinsin the field of caring for keratin materials such as the skin, and inparticular as an agent for treating acneic skin and in particular acneicskin having imperfections related to P. acnes.

The invention relates to a method for treating acneic skin using acomposition comprising a mixture of arthrofactins.

Common acne is a multifactor disease (face, shoulder region, arms andintertriginous regions). It is the main cause of the most common formsof dermatosis. It is important not to trivialize this disease and totreat it correctly, since it can have debilitating psychosocialconsequences, in particular because of the formation of scars.

In its mildest form, it affects almost every human being. Its frequencyis maximal at the age of puberty, but it can manifest itself for thefirst time from the age of 7 to 9, and may extend beyond the age of 40.It is common to still be suffering from acne after the age of 25.Moreover acne affects men as well as women.

Acne is a disease of the sebaceous gland of the follicle. The followingpathogenic factors play a determining role in the formation of acne:

-   -   Genetic predisposition.    -   Androgens.    -   Abnormally increased keratinization (keratinization disorder) in        the infundibular portion of the hair follicle. Indeed, in the        deepest parts of the infundibulum, the formation of a larger        than normal amount of keratinocytes is noted. These cells        differentiate into horny cells which gradually block the lumen        of the follicular canal. The physiological process of continuous        desquamation from the acro-infundibulum to the surface is        disrupted by the increased adhesion of the horny cells produced.        A hyperkeratotic plug constituting the comedone, the initial        lesion of acne, forms.    -   Bacterial infections responsible for the hydrolysis of free        fatty acids and inflammatory phenomena (papules and pustules).

The predominant three local microorganisms, Staphyloccus epidermidis,Malassezia furfur and Propionibacterium acnes, find an ideal nutritiveenvironment in the sebaceous follicle.

The clinical manifestations are characterized by a polymorphic picture.Interest is focussed here on the most common forms of acne, namely,comedonal acne (juvenile acne), papulo-pustular acne and/or nodularacne.

The retention lesions may be of open or closed comedone type (microcyst,microcomedone, whitehead). The inflammatory lesions derived from theretention lesions may be of the type such as papules, pustules, withindurated nodules, abscesses, fistulas or scar forms.

Evaluation Using the ECLA Scale

The clinical severity of acne has been determined using thesemi-quantitative scoring scale ECLA [acne lesion clinical evaluationscale].

This scale is made up of three factors:

TABLE I Presentation of the ECLA scale Factor 1 (F1): acne type andintensity; count on the the whole face Very Absent = Scarce = Low =Medium = High = high = 0 1 2 3 4 5 F1 R Open and None <5 5 to 9 10 to 1920 to 40 >40 R closed comedones (microcysts) Is Papules and None <5 5 to9 10 to 19 20 to 40 >40 Is pustules Ip Inflammatory None 1 2 3 4  ≠5 Ipnodules and cysts Score 1= Factor 2 (F2): extension and intensity of theacne; beyond the face. 0 1 2 3 Absent Low Medium High F2 Neck (N) Topcervical N zone Chest (C) Bottom cervical C zone Back (B) Top point of Bshoulder blade Arm (A) Bottom point of A shoulder blade Score 2= Factor3 (F3): scars - absent = 0; present = 1 Inflammatory Non-inflammatoryExcoriations IS NIS E Score 3= Final score: Score 1 + Score 2 + Score 3=The ECLA score is therefore between 0 and 36

For the purposes of the invention, the term “skin” is intended to denotethe entire epidermis of the human body. More particularly, the skinconsidered in the present invention is preferably the skin of the face,of the neckline, of the back or of the scalp, and preferably the skin ofthe face.

The expression “imperfections related to Propionibacterium acnes” isunderstood to mean open and/or closed comedones, microcysts, papules,pustules and also inflammatory nodules and cysts.

For the purposes of the invention, the term “treatment” is understood tomean curative and/or prophylactic treatment and preferably a curativetreatment.

For the purposes of the invention, the term “acneic skin” is intended tomean skin exhibiting acne with an ECLA score of between 1 and 36.

To combat acne, various compounds have already been proposed, which, bytopical application to the skin, are capable of reducing theproliferation of P. acnes.

Unfortunately, the treatments currently available are not completelysatisfactory, in particular from the viewpoint of the side effects whichare frequently associated therewith, such as irritative side effectswith certain topical agents, for instance retinoids and benzoylperoxides. Moreover, resistance of P. acnes to certain localantibacterial therapies is frequently observed.

There remains therefore the need for topically applied active agentswhich have an effect on the pathologies related to microorganisms of thePropionibacterium genus, and particularly Propionibacterium acnes, whileat the same time not having the drawbacks of the compounds known forthis use.

Moreover, the development of resistance of P. acnes against existingactive agents reveals the need to identify new molecules in order tomaintain over time an effective action on the inhibition of P. acnesgrowth.

Furthermore, there is an additional interest in having availablebiomolecules of biotechnological origin that are cosmetically active.Very few biomolecules of this type have however been proposed to date,in particular for the treatment of acneic skin.

The Applicant has demonstrated that by using a treatment method thatconsists in applying to acneic skin and in particular acneic skin havingimperfections related to the microorganism P. acnes, a compositioncomprising a mixture of arthrofactins, such a treatment method exhibitsactivity on the decrease or inhibition of microorganisms involved in thedevelopment of acne, especially Propionibacterium acnes.

The Applicant has indeed observed that a mixture of arthrofactinsaccording to the invention had a strong inhibitory activity on thegrowth of Propionibacterium acnes, and could therefore be used in adermatological composition for the treatment of acneic skin.

One subject of the present invention is therefore a method for treatingacneic skin and in particular acneic skin having imperfections relatedto Propionibacterium acnes, comprising the application to the acneicskin of a dermatological composition comprising, in a physiologicallyacceptable medium, at least one mixture of arthrofactins.

One subject of the invention is a mixture of arthrofactin or of adermatological composition containing at least one mixture ofarthrofactin for treating acneic skin and in particular acneic skinhaving imperfections related to microorganisms of the Propionibacteriumgenus, and particularly Propionibacterium acnes.

The present invention results from the unexpected discovery by theinventors that arthrofactin, a partially cyclic lipopeptide of thefamily of biosurfactants described in Lange et al. (2012) Chem Bio Chem13:2671-2675 and produced by Pseudomonas sp MIS 38 (Morikawa et al.(1993) J. Bacteriol. 175:6459-6466), and more particularly a mixture ofarthrofactins produced by Pseudomonas sp MIS 38, inhibits theproliferation of P. acnes, demonstrating an effect on acneic skin.

The mixture of arthrofactins produced by Pseudomonas sp MIS 38 asdescribed below makes it possible especially to provide, while at thesame time having an effect of treating acneic skin, compositions thathave good stability and/or that remain pleasant for the consumer, i.e.being sparingly tacky, having a pleasant feel, and/or having nodiscomfort sensations such as tautness.

The inventors discovered that the mixture of arthrofactins produced byPseudomonas sp MIS 38 as described below was a good agent for treatingacneic skin, and in particular acneic skin having imperfections relatedto P. acnes, this mixture having an effect of inhibiting the growth ofP. acnes.

Patent FR2898049 describes a cosmetic lip care method comprising theapplication to the lips of a composition comprising an emulsion of oilin a polar phase, said emulsion comprising at least one cycliclipopeptide capable of being obtained by fermentation of prokaryotes,the cyclic lipopeptide acting as emulsifier for stabilizing theemulsion. No anti-acne property of arthrofactin is however described inthis document.

International application WO9962482 itself describes a surfactant foruse in the external preparation of skin comprising a lipopeptide derivedfrom prokaryotes and having low skin penetrability and low skinirritability. No anti-acne property of arthrofactin is however describedin this document.

One subject of the present invention is therefore a method for treatingacneic skin and in particular acneic skin having imperfections relatedto P. acnes microorganisms, comprising the application to the acneicskin of a dermatological composition comprising, in a physiologicallyacceptable medium, at least one mixture of arthrofactins, said mixtureof arthrofactins comprising:

(i) arthrofactin A of formula (I) below:

R₁-D-Leu₁-D-Asp₂-D-allo-Thr₃-D-Leu₄-D-Leu₅-D-Ser₆-L-Leu₇-D-Ser₈-L-Ile₉-L-Ile₁₀-L-Asp₁₁  (I),

in which

-   -   the hydroxyl group of the D-allo-Thr₃ amino acid residue forms        an ester bond with the C-terminal carboxyl group of the L-Asp₁₁        amino acid residue, and    -   R₁ represents the group of formula (I′) below:

-   -   -   where R₁′ is a saturated alkyl chain of 5 to 8 carbon atoms;            and

(ii) at least one derivative of arthrofactin A, said derivative being offormula (II) below:

R-Xaa₁-Xaa₂-Xaa₃-Xaa₄-Xaa₅-Xaa₆-Xaa₇-Xaa₈-Xaa₉-Xaa₁₀-Xaa₁₁  (II)

in which

-   -   Xaa₁, Xaa₄, Xaa₅, Xaa₇, Xaa₉ and Xaa₁₀ each represent,        independently, D-Leu, L-Leu, D-Ile or L-Ile,    -   Xaa₂ and Xaa₁₁ each represent, independently, D-Asp, L-Asp,        D-Glu or L-Glu,    -   Xaa₃ represents D-Thr, L-Thr, D-allo-Thr or L-allo-Thr,    -   Xaa₆ and Xaa₈ each represent, independently, D-Ser, L-Ser, D-Gln        or L-Gln,    -   the hydroxyl group of the Xaa₃ amino acid residue forms an ester        bond with the C-terminal carboxyl group of the Xaa₁₁ amino acid        residue, and    -   R represents the group of formula (II′) below:

-   -   -   where R′ is a hydrocarbon chain of 5 to 9 carbon atoms,            optionally comprising at least one ethylenic unsaturation of            cis or trans configuration;            for the treatment of acneic skin.

Another subject of the present invention is a method for preventingand/or treating skin disorders related to Propionibacterium acnes,comprising the application to the acneic skin of a dermatologicalcomposition comprising, in a physiologically acceptable medium, at leastone mixture of arthrofactins, said mixture of arthrofactins comprising:(i) arthrofactin A of formula (I) below:

R₁-D-Leu₁-D-Asp₂-D-allo-Thr₃-D-Leu₄-D-Leu₅-D-Ser₆-L-Leu₇-D-Ser₈-L-Ile₉-L-Ile₁₀-L-Asp₁₁  (I),

in which

-   -   the hydroxyl group of the D-allo-Thr₃ amino acid residue forms        an ester bond with the C-terminal carboxyl group of the L-Asp₁₁        amino acid residue, and    -   R₁ represents the group of formula (I′) below:

-   -   -   where R₁′ is a saturated alkyl chain of 5 to 8 carbon atoms;            and

(ii) at least one derivative of arthrofactin A, said derivative being offormula (II) below:

R-Xaa₁-Xaa₂-Xaa₃-Xaa₄-Xaa₅-Xaa₆-Xaa₇-Xaa₈-Xaa₉-Xaa₁₀-Xaa₁₁  (II)

in which

-   -   Xaa₁, Xaa₄, Xaa₅, Xaa₇, Xaa₉ and Xaa₁₀ each represent,        independently, D-Leu, L-Leu, D-Ile or L-Ile,    -   Xaa₂ and Xaa₁₁ each represent, independently, D-Asp, L-Asp,        D-Glu or L-Glu,    -   Xaa₃ represents D-Thr, L-Thr, D-allo-Thr or L-allo-Thr,    -   Xaa₆ and Xaa₈ each represent, independently, D-Ser, L-Ser, D-Gln        or L-Gln,    -   the hydroxyl group of the Xaa₃ amino acid residue forms an ester        bond with the C-terminal carboxyl group of the Xaa₁₁ amino acid        residue, and    -   R represents the group of formula (II′) below:

-   -   -   where R′ is a hydrocarbon chain of 5 to 9 carbon atoms,            optionally comprising at least one ethylenic unsaturation of            cis or trans configuration;        -   for the treatment of acneic skin.

The composition comprising said arthrofactin mixture is intended fortopical application to the skin and in particular to the skin of theface.

According to one particular variant of the invention, the compositionfor treating acneic skin and in particular acneic skin havingimperfections related to Propionibacterium acnes, additionally comprisesa physiologically acceptable medium and at least one compound chosenfrom thickeners, preservatives, fragrances, bactericides, pigments,colorants, organic solvents including in particular C₁-C₆ alcohols andC₂-C₁₀ carboxylic acid esters, carbon-based and/or silicone oils whetherthey are of mineral, animal and/or plant origin, waxes, fillers,emulsifiers, co-emulsifiers, photoprotective agents which are active inthe UV-A and/or UV-B regions, also referred to as UV screening agents,polymers, and hydrophilic or lipophilic gelling agents.

According to one particular embodiment, one subject of the presentinvention is a method for treating acneic skin and in particular acneicskin having imperfections related to Propionibacterium acnes, comprisingthe application to the acneic skin of a dermatological compositioncomprising, in a physiologically acceptable medium, at least one mixtureof arthrofactins, said mixture of arthrofactins comprising: (i)arthrofactin A of formula (I) as described above

-   -   and    -   (ii) at least one derivative of arthrofactin A, said derivative        being of formula (II) as described above,        the composition additionally comprising a physiologically        acceptable medium and at least one compound chosen from        thickeners, preservatives, fragrances, bactericides, organic        solvents including in particular C₁-C₆ alcohols and C₂-C₁₀        carboxylic acid esters, and carbon-based and/or silicone oils        whether they are of mineral, animal and/or plant origin.

The mixture of arthrofactins as defined below, or the compositionscomprising it, may be used once or repeatedly, such as one to two timesper day for example, preferably over a period of at least one week, andmore particularly of at least four weeks.

DETAILED DESCRIPTION OF THE INVENTION

The mixture of arthrofactins according to the invention, having theanti-acne properties described here, is a mixture of arthrofactinscomprising

(i) arthrofactin A of formula (I) below:

R₁-D-Leu₁-D-Asp₂-D-allo-Thr₃-D-Leu₄-D-Leu₅-D-Ser₆-L-Leu₇-D-Ser₈-L-Ile₉-L-Ile₁₀-L-Asp₁₁  (I),

in which

-   -   the hydroxyl group of the D-allo-Thr₃ amino acid residue forms        an ester bond with the C-terminal carboxyl group of the L-Asp₁₁        amino acid residue, and    -   R₁ represents the group of formula (I′) below:

-   -   -   where R₁′ is a saturated alkyl chain of 5 to 8 carbon atoms,            in particular 7 carbon atoms; and

(ii) at least one derivative of arthrofactin A, said derivative being offormula (II) below:

R-Xaa₁-Xaa₂-Xaa₃-Xaa₄-Xaa₅-Xaa₆-Xaa₇-Xaa₈-Xaa₉-Xaa₁₀-Xaa₁₁  (II)

in which

-   -   Xaa₁, Xaa₄, Xaa₅, Xaa₇, Xaa₉ and Xaa₁₀ each represent,        independently, D-Leu, L-Leu, D-Ile or L-Ile,    -   Xaa₂ and Xaa₁₁ each represent, independently, D-Asp, L-Asp,        D-Glu or L-Glu,    -   Xaa₃ represents D-Thr, L-Thr, D-allo-Thr or L-allo-Thr,    -   Xaa₆ and Xaa₈ each represent, independently, D-Ser, L-Ser, D-Gln        or L-Gln,    -   the hydroxyl group of the Xaa₃ amino acid residue forms an ester        bond with the C-terminal carboxyl group of the Xaa₁₁ amino acid        residue, and    -   R represents the group of formula (II′) below:

-   -   -   where R′ is a hydrocarbon chain of 5 to 9 carbon atoms,            optionally comprising at least one ethylenic unsaturation of            cis or trans configuration.

Within the context of the invention, the amino acids preceded by thesymbol “D-” are amino acids of D configuration, whilst the amino acidspreceded by the symbol “L-” are amino acids of L configuration.

The term “D-allo-Thr” denotes the stereoisomer of threonine of (2R, 3R)configuration, whilst the term “L-allo-Thr” denotes the stereoisomer ofthreonine of (2S, 3S) configuration.

An “alkyl chain” is understood here to mean a saturated hydrocarbonchain.

In one particular embodiment, the R₁′ group as defined above is an alkylchain of 5, 6, 7 or 8 carbon atoms and preferably is an alkyl chain of 7carbon atoms.

In one particular embodiment, the R′ group is a hydrocarbon chain of 5,6, 7, 8 or 9 carbon atoms, optionally comprising at least one ethylenicunsaturation of cis or trans configuration. In one particularembodiment, the R′ group as defined above is a saturated alkyl chain of5, 6, 7, 8 or 9 carbon atoms. In another embodiment, the R′ group is ahydrocarbon chain of 5, 6, 7, 8 or 9 carbon atoms comprising at leastone ethylenic unsaturation of cis or trans configuration, preferablycomprising exactly one ethylenic unsaturation of cis or transconfiguration.

In one particular embodiment, the R′ group is an alkyl chain of 7 or 9carbon atoms, optionally comprising at least one ethylenic unsaturationof cis or trans configuration. In one particular embodiment, the R′group is a saturated alkyl chain of 7 or 9 carbon atoms. In anotherembodiment, the R′ group is an alkyl chain of 7 or 9 carbon atomscomprising at least one ethylenic unsaturation of cis or transconfiguration, preferably comprising exactly one ethylenic unsaturationof cis or trans configuration.

In one particular embodiment, the R′ group is a saturated alkyl chain of7 carbon atoms. In another particular embodiment, the R′ group is ahydrocarbon chain of 7 carbon atoms comprising at least one ethylenicunsaturation of cis or trans configuration, preferably comprisingexactly one ethylenic unsaturation of cis or trans configuration.

In another particular embodiment, the R′ group is a saturated alkylchain of 9 carbon atoms. In another particular embodiment, the R′ groupis a hydrocarbon chain of 9 carbon atoms comprising at least oneethylenic unsaturation of cis or trans configuration, preferablycomprising exactly one ethylenic unsaturation of cis or transconfiguration.

In one particular embodiment, the Xaa₁, Xaa₄, Xaa₅, Xaa₇, Xaa₉ and Xaa₁₀amino acids as defined above each represent, independently, D-Leu orL-Leu. In another particular embodiment, the Xaa₁, Xaa₄, Xaa₅, Xaa₇,Xaa₉ and Xaa₁₀ amino acids each represent, independently, D-Ile orL-Ile.

In another embodiment, the Xaa₁, Xaa₄ and Xaa₅ amino acids eachrepresent, independently, D-Leu or D-Ile. In another particularembodiment, the Xaa₇, Xaa₉ and Xaa₁₀ amino acids each represent,independently, L-Leu or L-Ile.

In a preferred embodiment, the Xaa₁, Xaa₄ and Xaa₅ amino acids eachrepresent D-Leu. In another preferred embodiment, the Xaa₇ amino acidrepresents L-Leu. In another preferred embodiment, the Xaa₅, and Xaa₁₀amino acids each represent L-Ile.

In one particularly preferred embodiment, the Xaa₁, Xaa₄ and Xaa₅ aminoacids each represent D-Leu, the Xaa₇ amino acid represents L-Leu, andthe Xaa₉ and Xaa₁₀ amino acids each represent L-Ile.

In one particular embodiment, the Xaa₂ and Xaa₁₁ amino acids eachrepresent, independently, D-Asp or L-Asp. In another particularembodiment, the Xaa₂ and Xaa₁₁ amino acids each represent,independently, D-Glu or L-Glu. In another particular embodiment, theXaa₂ and Xaa₁₁ amino acids each represent, independently, D-Asp orD-Glu. In a preferred embodiment, the Xaa₂ amino acid represents D-Asp.In a preferred embodiment, the Xaa₁₁ amino acid represents L-Asp orL-Glu. In a more preferred embodiment, the Xaa₂ amino acid representsD-Asp and the Xaa₁₁ amino acid represents L-Asp or L-Glu.

In one particular embodiment, the Xaa₃ amino acid represents D-Thr orL-Thr. In another particular embodiment, the Xaa₃ amino acid representsD-allo-Thr or L-allo-Thr. In another particular embodiment, the Xaa₃amino acid represents D-Thr or D-allo-Thr. In a preferred embodiment,the Xaa₃ amino acid represents D-allo-Thr.

In one particular embodiment, the Xaa₆ and Xaa₈ amino acids eachrepresent, independently, D-Ser or L-Ser. In another particularembodiment, the Xaa₆ and Xaa₈ amino acids each represent, independently,D-Gln or L-Gln. In another embodiment, the Xaa₆ and Xaa₈ amino acidseach represent, independently, D-Ser or D-Gln. In a preferredembodiment, the Xaa₆ and Xaa₈ amino acids each represent D-Ser.

Thus, in one particular embodiment, the at least one derivative ofarthrofactin A is of formula (II) below:

R-Xaa₁-Xaa₂-Xaa₃-Xaa₄-Xaa₅-Xaa₆-Xaa₇-Xaa₈-Xaa₉-Xaa₁₀-Xaa₁₁  (II)

in which

-   -   Xaa₁, Xaa₄, Xaa₅, Xaa₇, Xaa₉ and Xaa₁₀ each represent,        independently, D-Leu, L-Leu, D-Ile or L-Ile,    -   Xaa₂ and Xaa₁₁ each represent, independently, D-Asp, L-Asp,        D-Glu or L-Glu,    -   Xaa₃ represents D-Thr, L-Thr, D-allo-Thr or L-allo-Thr,    -   Xaa₆ and Xaa₈ each represent, independently, D-Ser, L-Ser, D-Gln        or L-Gln,    -   the hydroxyl group of the Xaa₃ amino acid residue forms an ester        bond with the C-terminal carboxyl group of the Xaa₁₁ amino acid        residue, and    -   R represents the group of formula (II′) below:

-   -   where R′ is a saturated alkyl chain of 7 carbon atoms, a        hydrocarbon chain of 7 carbon atoms comprising exactly one        ethylenic unsaturation of cis or trans configuration, a        saturated alkyl chain of 9 carbon atoms, or a hydrocarbon chain        of 9 carbon atoms comprising exactly one ethylenic unsaturation        of cis or trans configuration.

In another particular embodiment, the at least one derivative ofarthrofactin A is of formula (II) below:

R-Xaa₁-Xaa₂-Xaa₃-Xaa₄-Xaa₅-Xaa₆-Xaa₇-Xaa₈-Xaa₉-Xaa₁₀-Xaa₁₁  (II)

in which

-   -   Xaa₁, Xaa₄, Xaa₅, Xaa₇, Xaa₉ and Xaa₁₀ each represent,        independently, D-Leu, L-Leu, D-Ile or L-Ile,    -   Xaa₂ and Xaa₁₁ each represent, independently, D-Asp, L-Asp,        D-Glu or L-Glu,    -   Xaa₃ represents D-Thr, L-Thr, D-allo-Thr or L-allo-Thr,    -   Xaa₆ and Xaa₈ each represent, independently, D-Ser, L-Ser, D-Gln        or L-Gln,    -   the hydroxyl group of the Xaa₃ amino acid residue forms an ester        bond with the C-terminal carboxyl group of the Xaa₁₁ amino acid        residue, and    -   R represents the group of formula (II′) below:

-   -   where R′ is a saturated alkyl chain of 7 carbon atoms, a        saturated alkyl chain of 9 carbon atoms, or a hydrocarbon chain        of 9 carbon atoms comprising exactly one ethylenic unsaturation        of cis or trans configuration.

In another particular embodiment, the at least one derivative ofarthrofactin A is of formula (II) below:

R-Xaa₁-Xaa₂-Xaa₃-Xaa₄-Xaa₅-Xaa₆-Xaa₇-Xaa₈-Xaa₉-Xaa₁₀-Xaa₁₁  (II)

in which

-   -   Xaa₁, Xaa₄ and Xaa₅ each represent D-Leu, Xaa₇ represents L-Leu,        and Xaa₉ and Xaa₁₀ each represent L-Ile,    -   Xaa₂ represents D-Asp and Xaa₁₁ represents L-Asp or L-Glu,    -   Xaa₃ represents D-allo-Thr,    -   Xaa₆ and Xaa₈ each represent D-Ser    -   the hydroxyl group of the Xaa₃ amino acid residue forms an ester        bond with the C-terminal carboxyl group of the Xaa₁₁ amino acid        residue, and    -   R represents the group of formula (II′) below:

-   -   where R′ is an alkyl chain of 5 to 9 carbon atoms, optionally        comprising at least one ethylenic unsaturation of cis or trans        configuration.

In another particular embodiment, the at least one derivative ofarthrofactin A is of formula (II) below:

R-Xaa₁-Xaa₂-Xaa₃-Xaa₄-Xaa₅-Xaa₆-Xaa₇-Xaa₈-Xaa₉-Xaa₁₀-Xaa₁₁  (II)

in which

-   -   Xaa₁, Xaa₄ and Xaa₅ each represent D-Leu, Xaa₇ represents L-Leu,        and Xaa₉ and Xaa₁₀ each represent L-Ile,    -   Xaa₂ represents D-Asp and Xaa₁₁ represents L-Asp or L-Glu,    -   Xaa₃ represents D-allo-Thr,    -   Xaa₆ and Xaa₈ each represent D-Ser    -   the hydroxyl group of the Xaa₃ amino acid residue forms an ester        bond with the C-terminal carboxyl group of the Xaa₁₁ amino acid        residue, and    -   R represents the group of formula (II′) below:

-   -   where R′ is a saturated alkyl chain of 7 carbon atoms, a        saturated alkyl chain of 9 carbon atoms, or a hydrocarbon chain        of 9 carbon atoms comprising exactly one ethylenic unsaturation        of cis or trans configuration.

In one particular embodiment, said at least one derivative ofarthrofactin A is chosen from the group consisting of arthrofactin B,arthrofactin C, arthrofactin D and mixtures thereof,

arthrofactin B being of formula (III) below:

R₁-D-Leu₁-D-Asp₂-D-allo-Thr₃-D-Leu₄-D-Leu₅-D-Ser₆-L-Leu₇-D-Ser₈-L-Ile₉-L-Ile₁₀-L-Glu₁₁  (III),

-   -   in which        -   the hydroxyl group of the D-allo-Thr₃ amino acid residue            forms an ester bond with the C-terminal carboxyl group of            the L-Glu₁₁ amino acid residue, and        -   R₁ is as defined in Claim 1;

arthrofactin C being of formula (IV) below:

R₂-D-Leu₁-D-Asp₂-D-allo-Thr₃-D-Leu₄-D-Leu₅-D-Ser₆-L-Leu₇-D-Ser₈-L-Ile₉-L-Ile₁₀-L-Asp₁₁  (IV),

-   -   in which        -   the hydroxyl group of the D-allo-Thr₃ amino acid residue            forms an ester bond with the C-terminal carboxyl group of            the L-Asp₁₁ amino acid residue, and        -   R₂ represents the group of formula (IV′) below:

-   -   where R₂′ is an alkyl chain of 9 carbon atoms comprising exactly        one unsaturation;

arthrofactin D being of formula (V) below:

R₃-D-Leu₁-D-Asp₂-D-allo-Thr₃-D-Leu₄-D-Leu₅-D-Ser₆-L-Leu₇-D-Ser₈-L-Ile₉-L-Ile₁₀-L-Asp₁₁  (V),

-   -   in which        -   the hydroxyl group of the D-allo-Thr₃ amino acid residue            forms an ester bond with the C-terminal carboxyl group of            the L-Asp₁₁ amino acid residue, and        -   R₃ represents the group of formula (V′) below:

-   -   where R₃′ is a saturated alkyl chain of 9 carbon atoms.

According to one particular embodiment of the invention, the mixture ofarthrofactins having the anti-acne properties described here, is amixture of arthrofactins comprising:

-   -   (i) arthrofactin A of formula (IA) below:

-   -   (ii) at least one derivative of arthrofactin A, said derivative        being of formula (IIA) and/or (IIB) and/or (IIC) below:

According to one particular embodiment of the invention, the activeingredient of the composition according to the invention, having theproperties, especially anti-acne properties, described here, is amixture of arthrofactins comprising:

-   -   (i) arthrofactin A of formula (IA)    -   (ii) a derivative of arthrofactin A of formula (IIA)    -   (iii) a derivative of arthrofactin A of formula (IIB)    -   (iv) a derivative of arthrofactin A of formula (IIC)

The R, R₁, R₂ and R₃ groups as defined above are bonded to theN-terminal end of the 1^(st) amino acid (D-Leu₁ or Xaa₁) of the peptidesequence defined above.

In a particularly preferred embodiment of the invention, thearthrofactin mixture according to the invention predominantly comprisesarthrofactin A.

The expression “to predominately comprise arthrofactin A” is understoodhere to mean that the arthrofactin A represents at least 50% by weight,preferably at least 60%, preferably at least 70%, of the mixture ofarthrofactins, in particular of the assembly composed of arthrofactin Aand derivatives of arthrofactin A as defined above.

The inventors have shown that the mixture of arthrofactins as definedabove was typically obtained by fermentation with the Pseudomonas sp.MIS38 strain.

Thus, in one particular embodiment, the mixture of arthrofactinsaccording to the invention is capable of being obtained by fermentationwith the Pseudomonas sp. MIS38 strain.

The Pseudomonas sp. MIS38 strain is well known to a person skilled inthe art and is for example described in Morikawa et al. (1993) J.Bacteriol. 175:6459-6466.

The mixture of arthrofactins according to the invention may be obtainedby fermentation with the Pseudomonas sp. MIS38 strain, by anyfermentation technique well known to a person skilled in the art, forexample by the fermentation technique described in Washio et al. (2010)Biosci. Biotechnol. Biochem. 74:992-999. Typically, the Pseudomonas sp.MIS38 strain may be grown in the LB medium (1% Bacto tryptone, 0.5%yeast extract, 0.5% NaCl, pH 7.2) at 30° C. for 48 h. The culture maythen be centrifuged and the supernatant recovered and concentrated, forexample by ultrafiltration. The mixture of arthrofactins may then bepurified from this supernatant by solid-phase extraction orliquid-liquid extraction.

The mixture of arthrofactins according to the invention may be obtainedin particular according to the method described in Chem Bio Chem, 2012,13, 2671-2675.

Composition

According to one particular embodiment of the invention, the cosmeticand/or pharmaceutical, in particular dermatological compositioncomprising at least one arthrofactin or a mixture of arthrofactins asdescribed above is intended for topical administration to the skin andmore particularly to the skin of the face.

The mixture of arthrofactins according to the invention may be presentin the dermatological compositions according to the invention in anamount which may be between 0.01% and 10% by weight, preferably between0.1% and 5% by weight, preferably between 0.5% and 3% by weight, morepreferably between 1% and 2% by weight, relative to the total weight ofthe composition.

The composition additionally comprises a physiologically acceptablemedium, i.e. a medium that has no unpleasant odour, colour orappearance, and that does not cause the user any discomfort such asunacceptable stinging or tautness. In particular, the composition issuitable for topical application to the skin.

A “physiologically acceptable medium” is thus understood to mean amedium that is compatible with human keratin materials and in particularwith the skin of the body or of the face.

The composition according to the invention may comprise any of thecosmetic adjuvants normally used in the field of application envisioned.

The invention also relates to a composition comprising, in aphysiologically acceptable medium, a mixture of arthrofactins as definedabove and one or more additional active agents other than arthrofactinof formula (I) and arthrofactin derivatives of formula (II).

Galenical Forms These compositions in which the compounds used accordingto the invention may be implemented are useful in particular for thecare of the skin and particularly for treating acneic skin.

A composition used according to the invention is advantageously suitablefor topical application to the skin.

For topical application to the skin, a composition according to theinvention may be in any galenical form conventionally intended for thistype of application and especially in the form of aqueous gels oraqueous or aqueous-alcoholic solutions. By adding a fatty or oily phase,they may also be in the form of dispersions of lotion type, emulsions ofliquid or semi-liquid consistency of milk type, obtained by dispersing afatty phase in an aqueous phase (O/W) or vice versa (W/O), orsuspensions or emulsions of soft, semi-solid or solid consistency of thecream or gel type, or alternatively multiple emulsions (W/O/W or O/W/O),microemulsions, vesicular dispersions of ionic and/or nonionic type, orwax/aqueous phase dispersions. These compositions are prepared accordingto the usual methods.

Aqueous Phase

The compositions according to the invention intended for cosmetic usemay comprise at least one aqueous phase. They are in particularformulated as aqueous lotions or as water-in-oil or oil-in-wateremulsions or as multiple emulsions (oil-in-water-in-oil orwater-in-oil-in-water triple emulsions (such emulsions are known anddescribed, for example, by C. Fox in “Cosmetics and Toiletries”—November1986—Vol. 101—pages 101-112)).

The aqueous phase of said compositions contains water and generallyother water-soluble or water-miscible solvents. The water-soluble orwater-miscible solvents comprise short-chain, for example C₁-C₄,monoalcohols such as ethanol and isopropanol; diols or polyols.

The compositions according to the invention preferably have a pH rangingfrom 3 to 9, depending on the chosen support.

When the composition(s) are in emulsion form, they generally contain,depending on the nature of the emulsion, one or more emulsifyingsurfactants.

The total amount of emulsifiers will preferably be, in thecomposition(s) according to the invention, in active material contentsranging from 1% to 8% by weight and more particularly from 2% to 6% byweight relative to the total weight of the composition.

Fatty Phase

The compositions according to the invention may contain at least onewater-immiscible organic liquid phase, known as a fatty phase. Thisphase generally comprises one or more hydrophobic compounds which rendersaid phase water-immiscible. Said phase is liquid (in the absence ofstructuring agent) at room temperature (20-25° C.). Preferentially, thewater-immiscible organic liquid phase in accordance with the inventiongenerally comprises at least one volatile oil and/or non-volatile oiland optionally at least one structuring agent.

The term “oil” means a fatty substance that is liquid at roomtemperature (25° C.) and atmospheric pressure (760 mmHg, i.e. 1.05×10⁵Pa). The oil may be volatile or non-volatile.

For the purposes of the invention, the term “volatile oil” means an oilthat is capable of evaporating on contact with the keratin material,such as the skin, in less than one hour, at room temperature andatmospheric pressure. The volatile oils of the invention are volatilecosmetic oils, which are liquid at room temperature, having a non-zerovapour pressure, at room temperature and atmospheric pressure, rangingin particular from 0.13 Pa to 40 000 Pa (10⁻³ to 300 mmHg), inparticular ranging from 1.3 Pa to 13 000 Pa (0.01 to 100 mmHg) and moreparticularly ranging from 1.3 Pa to 1300 Pa (0.01 to 10 mmHg).

The term “non-volatile oil” means an oil that remains on the keratinmaterial, such as the skin, at room temperature and atmospheric pressurefor at least several hours and that especially has a vapour pressure ofless than 10⁻³ mmHg (0.13 Pa).

The oil may be chosen from any physiologically acceptable oil and inparticular cosmetically acceptable oil, especially mineral, animal,plant or synthetic oils; in particular volatile or non-volatilehydrocarbon-based oils and/or silicone oils and/or fluoro oils, andmixtures thereof.

More precisely, the term “hydrocarbon-based oil” means an oil mainlycomprising carbon and hydrogen atoms and optionally one or morefunctions chosen from hydroxyl, ester, ether and carboxylic functions.Generally, the oil has a viscosity of from 0.5 to 100 000 mPa·s,preferably from 50 to 50 000 mPa·s and more preferably from 100 to 300000 mPa·s.

As examples of volatile oils that may be used in the invention, mentionmay be made of:

-   -   volatile hydrocarbon-based oils chosen from hydrocarbon-based        oils containing from 8 to 16 carbon atoms, and especially C₈-C₁₆        isoalkanes of petroleum origin (also known as isoparaffins).

As examples of non-volatile oils that may be used in the invention,mention may be made of:

-   -   hydrocarbon-based plant oils such as liquid triglycerides of        fatty acids of 4 to 24 carbon atoms, for instance        caprylic/capric acid triglycerides such as those sold by the        company Stearineries Dubois or those sold under the names        Miglyol 810, 812 and 818 by the company Dynamit Nobel, and        jojoba oil,    -   linear or branched hydrocarbons, of mineral or synthetic origin,        such as liquid paraffins and derivatives thereof, petroleum        jelly, polydecenes, polybutenes, hydrogenated polyisobutene such        as Parleam, or squalane;    -   synthetic ethers having from 10 to 40 carbon atoms;    -   synthetic esters such as isononyl isononanoate, isopropyl        myristate, isopropyl palmitate or C₁₂ to C₁₅ alkyl benzoate;    -   silicone oils such as linear (dimethicone) or cyclic        (cyclomethicone) non-volatile polydimethylsiloxanes (PDMSs).

The compositions according to the invention may also comprise one ormore adjuvants. A person skilled in the art will take care to selectthis or these optional additional compounds such that the advantageousproperties intrinsically associated with the composition in accordancewith the invention are not, or are not substantially, adversely affectedby the envisaged addition(s).

These optional adjuvants may be present in the composition in aproportion of from 0.001% to 80% by weight and in particular from 0.1%to 40% by weight relative to the total weight of the composition.

Depending on their nature, these adjuvants may be introduced into thefatty phase or into the aqueous phase of the composition or into lipidvesicles. In any case, these adjuvants, and the proportions thereof,will be chosen by those skilled in the art such that the advantageousproperties of the mixture according to the invention are not, or are notsubstantially, adversely affected by the envisaged addition.

Hydrophilic gelling agents or thickeners that may be mentioned includecarboxyvinyl polymers such as carbomer, acrylic copolymers such asacrylate/alkyl acrylate copolymers, polyacrylamides such as the mixtureof polyacrylamide, C13-14 isoparaffin and laureth-7 sold under the nameSepigel 305^(e) by the company SEPPIC, polysaccharides such as cellulosederivatives (for example hydroxyalkyl celluloses, in particularhydroxypropyl cellulose and hydroxyethyl cellulose), natural gums suchas guar gum, locust bean gum and xanthan gum, and clays; lipophilicgelling agents or thickeners that may be mentioned include modifiedclays such as bentones, metal salts of fatty acids, hydrophobic silica,ethyl cellulose and polyethylene.

When the composition is an emulsion, the proportion of the fatty phasemay be from 5% to 80% by weight and preferably from 8% to 50% by weightrelative to the total weight of the composition. The emulsifier and thecoemulsifier may be present in a proportion ranging from 0.3% to 30% byweight, preferably from 0.5% to 20% by weight relative to the totalweight of the composition.

The composition according to the invention may be more or less fluid andmay have the appearance of a white or coloured cream, an ointment, amilk, a lotion, a serum, a paste, a gel or a foam. It may optionally beapplied in the form of an aerosol. It may also be in solid form, inparticular in stick form. It may also be on a support, for example onwipes such as makeup remover wipes.

The expressions “between . . . and . . . ” and “ranging from . . . to .. . ” or “at least of . . . ” should be understood to mean limitsincluded, unless otherwise specified.

Throughout the text hereinbelow, the percentages are given on a weightbasis, unless otherwise mentioned.

The examples that follow illustrate the invention, and are given purelyas nonlimiting illustrations.

Examples Example 1: Preparation of a Mixture of Arthrofactins Accordingto the Invention

The MIS38 strain was grown in a King'B medium at 28° C., 120 rpm and 4vvm. At the end of the fermentation, the culture medium was clarified bycentrifugation and the supernatant obtained was concentrated byultrafiltration (MWCO 10 kDa). The control of the transmembrane pressurein an appropriate concentration range makes it possible to measure aconcentration 7 times higher in the supernatant, this supernatant isthen diafiltered twice in order to eliminate the residual contaminationsof the culture medium. This fraction is then concentrated to drynessuntil a dry powder is obtained.

The fraction contains a mixture of arthofactin, in particular itcontains arthrofactin A of formula (IA) below:

-   -   +3 arthrofactin A derivatives of formulae (IIA), (IIB), (IIC)        below:

Example 2: The Arthrofactin Mixture According to the Invention has anAnti-Acne Property

This example shows that the arthrofactin mixture according to theinvention described in example 1 has an inhibitory activity onPropionibacterium acnes, which is responsible for acne.

The strain of Propionibacterium acnes ATCC 6919 initially kept at −20°C. in glycerol containing a culture broth was precultured in LB mediumwith stirring (160 rpm) at 30° C. After incubating for 16 hours, thecultures were centrifuged at 10 000 rpm for 5 min, and the cellularpellets were washed twice with PBS, before being inoculated at aconcentration of 5×10⁹ CFU per plate in a 100 mm diameter petri dishcontaining 20 m of reinforced medium (RCM) supplemented with 1.5% ofagarose at supercooling temperature. After solidification, at leastthree 6 mm discs of filter paper were placed on the surface of the agarlayer. Control solutions and solutions of 0.5% and 1% of mixture ofarthrofactins were prepared in a 1,3-propanediol/PBS (1/1, v/v) vehicle.10 μl of each sample to be tested were deposited on the discs. Lastly,the plates were incubated anaerobically for 72 h at 37° C.

At the end of the incubation period, the antagonist activity wasmeasured as the diameter of the clear zone of growth inhibition andrecorded as being the diameter of the inhibition zone in mm. 0.01%triclosan was used as positive control for the antibacterial activityand the vehicle served as negative control. Tests were carried out intriplicate.

An inhibitory activity of the arthrofactin mixture at 0.5% and 1% on theP. acnes strain is observed.

Example 3: Compositions for Topical Application

The following composition, for topical application, was prepared in theform of a

Weight % Compound from Example 1  1% Glyceryl monostearate 0.8% Cetylalcohol 2.0% Stearyl alcohol 5.0% Polyoxyethylene (20 OE) stearate 3.0%Crosslinked acrylic acid (Carbopol 941) 0.3% Caprylic/caprictriglycerides 12.0%  Preservatives qs Water qs 100.0% 

This cream is applied once or twice a day to acneic skin.

The exemplified formulation applied displays a good effect on acneicskin.

1. An arthrofactin mixture comprising (i) arthrofactin A of formula (I)below:R₁-D-Leu₁-D-Asp₂-D-allo-Thr₃-D-Leu₄-D-Leu₅-D-Ser₆-L-Leu₇-D-Ser₈-L-Ile₉-L-Ile₁₀-L-Asp₁₁  (I),in which the hydroxyl group of the D-allo-Thr₃ amino acid residue formsan ester bond with the C-terminal carboxyl group of the L-Asp₁₁ aminoacid residue, and R₁ represents the group of formula (I′) below:

where R₁′ is a saturated alkyl chain of 5 to 8 carbon atoms; and (ii) atleast one derivative of arthrofactin A, said derivative being of formula(II) below:R-Xaa₁-Xaa₂-Xaa₃-Xaa₄-Xaa₅-Xaa₆-Xaa₇-Xaa₈-Xaa₉-Xaa₁₀-Xaa₁₁  (II) inwhich Xaa₁, Xaa₄, Xaa₅, Xaa₇, Xaa₉ and Xaa₁₀ each represent,independently, D-Leu, L-Leu, D-Ile or L-Ile, Xaa₂ and Xaa₁₁ eachrepresent, independently, D-Asp, L-Asp, D-Glu or L-Glu, Xaa₃ representsD-Thr, L-Thr, D-allo-Thr or L-allo-Thr, Xaa₆ and Xaa₈ each represent,independently, D-Ser, L-Ser, D-Gln or L-Gln, the hydroxyl group of theXaa₃ amino acid residue forms an ester bond with the C-terminal carboxylgroup of the Xaa₁₁ amino acid residue, and R represents the group offormula (II′) below:

where R′ is an alkyl chain of 5 to 9 carbon atoms, optionally comprisingat least one unsaturation; for the treatment of acneic skin.
 2. Themixture according to claim 1, in which said acneic skin hasimperfections related to Propionibacterium acnes.
 3. The mixtureaccording to claim 1, for inhibiting the growth of Propionibacteriumacnes.
 4. The mixture according to claim 1, in which R₁′ is a saturatedalkyl chain of 7 carbon atoms.
 5. The mixture according to claim 1, inwhich said at least one derivative of arthrofactin A is chosen from thegroup consisting of arthrofactin B, arthrofactin C, arthrofactin D andmixtures thereof, arthrofactin B being of formula (III) below:R₁-D-Leu₁-D-Asp₂-D-allo-Thr₃-D-Leu₄-D-Leu₅-D-Ser₆-L-Leu₇-D-Ser₈-L-Ile₉-L-Ile₁₀-L-Glu₁₁  (III),in which the hydroxyl group of the D-allo-Thr₃ amino acid residue formsan ester bond with the C-terminal carboxyl group of the L-Glu₁₁ aminoacid residue, and arthrofactin C being of formula (IV) below:R₂-D-Leu₁-D-Asp₂-D-allo-Thr₃-D-Leu₄-D-Leu₅-D-Ser₆-L-Leu₇-D-Ser₈-L-Ile₉-L-Ile₁₀-L-Asp₁₁  (IV),in which the hydroxyl group of the D-allo-Thr₃ amino acid residue formsan ester bond with the C-terminal carboxyl group of the L-Asp₁₁ aminoacid residue, and R₂ represents the group of formula (IV′) below:

where R₂′ is an alkyl chain of 9 carbon atoms comprising exactly oneunsaturation; arthrofactin D being of formula (V) below:R₃-D-Leu₁-D-Asp₂-D-allo-Thr₃-D-Leu₄-D-Leu₅-D-Ser₆-L-Leu₇-D-Ser₈-L-Ile₉-L-Ile₁₀-L-Asp₁₁  (V),in which the hydroxyl group of the D-allo-Thr₃ amino acid residue formsan ester bond with the C-terminal carboxyl group of the L-Asp₁₁ aminoacid residue, and R₃ represents the group of formula (V′) below:

where R₃′ is a saturated alkyl chain of 9 carbon atoms.
 6. The mixtureaccording to claim 1, in which said arthrofactin mixture comprises (iii)arthrofactin A of formula (IA) below:

(iv) at least one derivative of arthrofactin A chosen from the compoundsof formula (IIA), (IIB) and/or (IIC) of formula(e) below:


7. The mixture according to claim 1, in which said at least onederivative of arthrofactin A is a mixture of said compounds of formula(IIA), (IIB) and (IIC).
 8. The mixture according to claim 1, in whichthe arthrofactin mixture predominantly comprises arthrofactin A.
 9. Themixture according to claim 1, in which said arthrofactin mixture iscapable of being obtained by fermentation with the Pseudomonas sp. MIS38strain.
 10. A composition comprising the arthrofactin mixture as definedin claim 1, for the treatment of acneic skin.
 11. The compositionaccording to claim 10, said composition being a dermatologicalcomposition.
 12. The composition according to claim 10, in which saidacneic skin has imperfections related to P. acnes.
 13. The compositionaccording to claim 10, for inhibiting the growth of Propionibacteriumacnes.
 14. The mixture according to claim 3, in which said at least onederivative of arthrofactin A is chosen from the group consisting ofarthrofactin B, arthrofactin C, arthrofactin D and mixtures thereof,arthrofactin B being of formula (III) below:R₁-D-Leu₁-D-Asp₂-D-allo-Thr₃-D-Leu₄-D-Leu₅-D-Ser₆-L-Leu₇-D-Ser₈-L-Ile₉-L-Ile₁₀-L-Glu₁₁  (III),in which the hydroxyl group of the D-allo-Thr₃ amino acid residue formsan ester bond with the C-terminal carboxyl group of the L-Glu₁₁ aminoacid residue, and R₁ is as defined in claim 1; arthrofactin C being offormula (IV) below:R₂-D-Leu₁-D-Asp₂-D-allo-Thr₃-D-Leu₄-D-Leu₅-D-Ser₆-L-Leu₇-D-Ser₈-L-Ile₉-L-Ile₁₀-L-Asp₁₁  (IV),in which the hydroxyl group of the D-allo-Thr₃ amino acid residue formsan ester bond with the C-terminal carboxyl group of the L-Asp₁₁ aminoacid residue, and R₂ represents the group of formula (IV′) below:

where R₂′ is an alkyl chain of 9 carbon atoms comprising exactly oneunsaturation; arthrofactin D being of formula (V) below:R₃-D-Leu₁-D-Asp₂-D-allo-Thr₃-D-Leu₄-D-Leu₅-D-Ser₆-L-Leu₇-D-Ser₈-L-Ile₉-L-Ile₁₀-L-Asp₁₁  (V),in which the hydroxyl group of the D-allo-Thr₃ amino acid residue formsan ester bond with the C-terminal carboxyl group of the L-Asp₁₁ aminoacid residue, and R₃ represents the group of formula (V′) below:

where R₃′ is a saturated alkyl chain of 9 carbon atoms.
 15. The mixtureaccording to claim 4, in which said arthrofactin mixture comprises (iii)arthrofactin A of formula (IA) below:

(iv) at least one derivative of arthrofactin A chosen from the compoundsof formula (IIA), (IIB) and/or (IIC) of formula(e) below:


16. The mixture according to claim 4, in which said arthrofactin mixturecomprises (iii) arthrofactin A of formula (IA) below:

(iv) at least one derivative of arthrofactin A chosen from the compoundsof formula (IIA), (IIB) and/or (IIC) of formula(e) below:


17. The mixture according to claim 4, in which said at least onederivative of arthrofactin A is a mixture of said compounds of formula(IIA), (IIB) and (IIC).
 18. The mixture according to claim 5, in whichsaid at least one derivative of arthrofactin A is a mixture of saidcompounds of formula (IIA), (IIB) and (IIC).
 19. The mixture accordingto claim 6, in which said at least one derivative of arthrofactin A is amixture of said compounds of formula (IIA), (IIB) and (IIC).
 20. Themixture according to claim 4, in which the arthrofactin mixturepredominantly comprises arthrofactin A.